It is known that the rosuvastatin {(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid calcium salt} as an active ingredient and the process for the synthesis thereof were first described in the patent EP 521,471.
It is also known that the marketed (under Crestor trade name) pharmaceutical composition is described among others in the WO 01/54668, WO 01/54669 or U.S. Pat. No. 6,316,460 patent specifications. According to these descriptions manufacturing of stable, solid pharmaceutical composition containing rosuvastatin can not be accomplished only by using pH adjuvant compounds, but the presence of inorganic salts of multivalent metals is also required to prevent the formation of lactone and oxidation decomposition products. In the pharmaceutical composition inorganic salts of multivalent metals (Ca, Mg, Zn, Al, Fe and the combinations thereof) are used as stabilizing additives such as aluminum, magnesium metasilicate, tribasic calcium phosphate, tribasic magnesium phosphate and tribasic aluminum phosphate. The marketed (under Crestor trade name) pharmaceutical composition contains tribasic calcium phosphate as stabilizing agent.
There are several patent applications and specifications dealing with the formulation problems of HMG-CoA reductase inhibitors, namely statins, in general. It is known from the literature that from among HMG-CoA reductase inhibitor, lipid-lowering drugs several compounds are sensitive to the properties of the micro-environment of the composition, in fact to light, to heat and humidity. The following patent specifications describe pharmaceutical compositions containing statins, among others rosuvastatin.
The WO 02/089788 describes statin containing pharmaceutical compositions the stability of which are provided by addition of amino sugars (for example N-methyl-glucoseamine). According to the description the advantage of the amino sugars versus inorganic alkali-earth metal salts is that they do not irritate the mucosa in the intestines.
The WO 00/53173 describes delayed-release pharmaceutical compositions containing statins as active ingredients, in which the release of the active ingredient in the stomach and the lactone formation under acidic conditions are prevented by special gel structure and enterically coated dosage form.
The WO 01/62230 describes a mannitol based granulate, in which the active ingredient statins are dissolved in NaOH solution and are added together with the granulating solution to the pharmaceutical dosage form.
According to the state of the art mentioned above there is a need for producing statin—in our case rosuvastatin—containing stable pharmaceutical compositions, which are easy to formulate.